Inhibitors of hepatitis c virus polymerase

Abstract

The present invention provides, among other things, compounds represented by the general Formula I: and pharmaceutically acceptable salts thereof, wherein X, Y, R 1A , R 1B , R 2 , and R 3 are as defined in classes and subclasses herein and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection.

1 .- 13 . (canceled) 
     
     
         14 . A method for treating or preventing hepatitis C virus infection or reactivation in a host, comprising administering to the host a therapeutic amount of at least one compound according to Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 one of X and Y is —CH— and the other is —N—; 
 R 1A  and R 1B  are independently hydrogen, —C 1-4 alkyl, —C 1-4 alkyl-C 3-7 cycloalkyl, —C 0-3 alkyl-C 5-7 heterocycloalkyl, —C 1-4 hydroxyalkyl, —C 1-4 haloalkyl, —C 1-4 alkyl-O—C 1-4 alkyl, —S(O) 2 C 1-4 alkyl, —S(O) 2 —R P , —S(O) 2 C 5-7 aryl-C 0-3 alkyl, —C 1-4 alkyl-S(O) 2 R L , —C 2-4 alkyl-NR M R N , —C 1-4 alkyl-R O , —C 0-3 alkyl-R P , —C 0-3 alkyl-C(O)C 1-4 alkyl, —C 0-3 alkyl-C(O)—C 1-4 hydroxyalkyl, —C 0-3 alkyl-C(O)—C 0-4 alkyl-R O , —C 0-3 alkyl-C(O)—C 0-4 alkyl-R P , —C(O)O—C 1-4 alkyl, —C 0-3 alkyl-C(O)O—C 0-4 alkyl-R O , —C 0-3 alkyl-C(O)O—C 0-4 alkyl-R P , —C 0-4 alkyl-C(O)OH, or —C 0-3 alkyl-C(O)—C 0-4 alkyl-NR M R N ;
 wherein:
 R L  is —C 1-4 alkyl, —C 3-5 cycloalkyl, —NR M R N ; 
 R M  and R N  are independently hydrogen, —C 1-4 alkyl, or R M  and R N  together with the atoms to which they are attached can form a 4- to 6-membered ring; 
 R O  is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, in each case monocyclic or bicyclic, and optionally substituted with (a) one to three moieties independently selected from —C 1-4 alkyl, halogen, —NR M R N , and —C 1-4 haloalkyl, or (b) a 6-membered aryl or 5-6 membered heteroaryl, optionally substituted with one to three moieties independently selected from —C 1-4 alkyl, halogen, and —NR M R N ; and 
 R P  is a 5- to 6-membered cycloalkyl or heterocycloalkyl group, optionally substituted with a hydroxyl; 
 
 provided that at least one of R 1A  and R 1B  is hydrogen; 
 
 R 2  is —C 5-6 cycloalkyl, —C 5-6 cycloalkyl-C 1-3 alkyl optionally substituted with a halogen, —C 5-6 cycloalkenyl, —C 5-6 cycloalkenyl-C 1-3 alkyl optionally substituted with a halogen or —C 1-4 alkyl-C 3-5 cycloalkyl; and 
 R 3  is —R A —R B  or halo;
 wherein R A  is ethynyl, or phenyl optionally substituted with one or two halogens, and 
 wherein R B  is hydrogen, —C 1-6 alkyl, —C 0-3 alkyl-NR M R N , —NHC 1-3 alkyl-R Q , —N(R U )C(O)—R Q , —C(O)NR U R Q , carboxyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 0-3 alkyl-C 3-6 cycloalkyl, —C 1-4 alkoxy, -methyl-(C 1-4 alkoxy) 1-2 , —C 0-3 alkyl-NR S R T , —C 3-7 cycloalkyl-C 0-3 alkyl-R Q , —C 0-4 alkyl-R Q , —C 2-6 alkynyR Q , or —C 2-4 alkenyl-R Q ;
 wherein R Q  is a 5- to 9-membered monocyclic or bicyclic aryl or heteroaryl or a 3- to 7-membered cycloalkyl or heterocycloalkyl, optionally substituted with one or two —C 1-3 alkyl or —NR M R N ; 
 R S  and R T  are each independently hydrogen or —C 1-4 alkyl, or one of R S  and R T  is hydrogen and the other is —C(O)-5- to 9-membered aryl or heteroaryl; and 
 R U  is hydrogen or —C 1-4 alkyl; 
 
 provided that, if R A  is phenyl, then R B  appears at the para or meta position relative to the thiophene moiety; and 
 
 R 4  is hydrogen, —C 1-4 alkyl, —C 1-4 alkyl-OC(O)O—C 1-4 alkyl, —C 1-4 alkyl-OC(O)—C 1-4 alkyl, —C 1-4 alkyl-OC(O)O—C 3-6 cycloalkyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl-, —C 0-3 alkyl-C 5-6 aryl, or —C 1-4 alkyl-NR U R V ;
 wherein R U  and R V  are independently hydrogen or —C 1-4 alkyl. 
 
 
     
     
         15 . A method according to  claim 14 , wherein R 4  is hydrogen 
     
     
         16 . A method according to  claim 14 , further comprising administering to the host at least one other active agent selected from the group consisting of interferons, ribavirin, nucleoside HCV NS5B polymerase inhibitors, non-nucleoside HCV NS5B polymerase inhibitors, HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3 inhibitors, HCV NS3 helicase inhibitors, HCV NS4B inhibitors, and human cyclophilin inhibitors. 
     
     
         17 . A method for reducing a hepatitis C virus polymerase activity in a host, comprising administering to the host a therapeutic amount of at least one compound according to Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 one of X and Y is —CH— and the other is —N—; 
 R 1A  and R 1B  are independently hydrogen, —C 1-4 alkyl, —C 1-4 alkyl-C 3-7 cycloalkyl, —C 0-3 alkyl-C 5-7 heterocycloalkyl, —C 1-4 hydroxyalkyl, —C 1-4 haloalkyl, —C 1-4 alkyl-O—C 1-4 alkyl, —S(O) 2 C 1-4 alkyl, —S(O) 2 —R P , —S(O) 2 C 5-7 aryl-C 0-3 alkyl, —C 1-4 alkyl-S(O) 2 R L , —C 2-4 alkyl-NR M R N , —C 1-4 alkyl-R O , —C 0-3 alkyl-R P , —C 0-3 alkyl-C(O)C 1-4 alkyl, —C 0-3 alkyl-C(O)—C 1-4 hydroxyalkyl, —C 0-3 alkyl-C(O)—C 0-4 alkyl-R O , —C 0-3 alkyl-C(O)—C 0-4 alkyl-R P , —C(O)O—C 1-4 alkyl, —C 0-3 alkyl-C(O)O—C 0-4 alkyl-R O , —C 0-3 alkyl-C(O)O—C 0-4 alkyl-R P , —C 0-4 alkyl-C(O)OH, or —C 0-3 alkyl-C(O)—C 0-4 alkyl-NR M R N ;
 wherein:
 R L  is —C 1-4 alkyl, —C 3-5 cycloalkyl, —NR M R N ; 
 R M  and R N  are independently hydrogen, —C 1-4 alkyl, or R M  and R N  together with the atoms to which they are attached can form a 4- to 6-membered ring; 
 R O  is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, in each case monocyclic or bicyclic, and optionally substituted with (a) one to three moieties independently selected from —C 1-4 alkyl, halogen, —NR M R N , and —C 1-4 haloalkyl, or (b) a 6-membered aryl or 5-6 membered heteroaryl, optionally substituted with one to three moieties independently selected from —C 1-4 alkyl, halogen, and —NR M R N ; and 
 R P  is a 5- to 6-membered cycloalkyl or heterocycloalkyl group, optionally substituted with a hydroxyl; 
 
 provided that at least one of R 1A  and R 1B  is hydrogen; 
 
 R 2  is —C 5-6 cycloalkyl, —C 5-6 cycloalkyl-C 1-3 alkyl optionally substituted with a halogen, —C 5-6 cycloalkenyl, —C 5-6 cycloalkenyl-C 1-3 alkyl optionally substituted with a halogen or —C 1-4 alkyl-C 3-5 cycloalkyl; and 
 R 3  is —R A —R B  or halo;
 wherein R A  is ethynyl, or phenyl optionally substituted with one or two halogens, and 
 wherein R B  is hydrogen, —C 1-6 alkyl, —C 0-3 alkyl-NR M R N , —NHC 1-3 alkyl-R Q , —N(R U )C(O)—R Q , —C(O)NR U R Q , carboxyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 0-3 alkyl-C 3-6 cycloalkyl, —C 1-4 alkoxy, -methyl-(C 1-4 alkoxy) 1-2 , —C 0-3 alkyl-NR S R T , —C 3-7 cycloalkyl-C 0-3 alkyl-R Q , —C 0-4 alkyl-R Q , —C 2-6 alkynyR Q , or —C 2-4 alkenyl-R Q ;
 wherein R Q  is a 5- to 9-membered monocyclic or bicyclic aryl or heteroaryl or a 3- to 7-membered cycloalkyl or heterocycloalkyl, optionally substituted with one or two —C 1-3 alkyl or —NR M R N ; 
 R S  and R T  are each independently hydrogen or —C 1-4 alkyl, or one of R S  and R T  is hydrogen and the other is —C(O)-5- to 9-membered aryl or heteroaryl; and 
 R U  is hydrogen or —C 1-4 alkyl; 
 
 provided that, if R A  is phenyl, then R B  appears at the para or meta position relative to the thiophene moiety; and 
 
 R 4  is hydrogen, —C 1-4 alkyl, —C 1-4 alkyl-OC(O)O—C 1-4 alkyl, —C 1-4 alkyl-OC(O)—C 1-4 alkyl, —C 1-4 alkyl-OC(O)O—C 3-6 cycloalkyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl-, —C 0-3 alkyl-C 5-6 aryl, or —C 1-4 alkyl-NR U R V ;
 wherein R U  and R V  are independently hydrogen or —C 1-4 alkyl. 
 
 
     
     
         18 . A method according to  claim 17 , wherein R 4  is hydrogen. 
     
     
         19 . A method according to  claim 17 , further comprising administering to the host at least one other active agent selected from the group consisting of interferons, ribavirin, nucleoside HCV NS5B polymerase inhibitors, non-nucleoside HCV NS5B polymerase inhibitors, HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3 inhibitors, HCV NS3 helicase inhibitors, HCV NS4B inhibitors, and human cyclophilin inhibitors. 
     
     
         20 . A method for reducing hepatitis C virus replication in a host, comprising administering to the host a therapeutic amount of at least one compound according to Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 one of X and Y is —CH— and the other is —N—; 
 R 1A  and R 1B  are independently hydrogen, —C 1-4 alkyl, —C 1-4 alkyl-C 3-7 cycloalkyl, —C 0-3 alkyl-C 5-7 heterocycloalkyl, —C 1-4 hydroxyalkyl, —C 1-4 haloalkyl, —C 1-4 alkyl-O—C 1-4 alkyl, —S(O) 2 C 1-4 alkyl, —S(O) 2 —R P , —S(O) 2 C 5-7 aryl-C 0-3 alkyl, —C 1-4 alkyl-S(O) 2 R L , —C 2-4 alkyl-NR M R N , —C 1-4 alkyl-R O , —C 0-3 alkyl-R P , —C 0-3 alkyl-C(O)C 1-4 alkyl, —C 0-3 alkyl-C(O)—C 1-4 hydroxyalkyl, —C 0-3 alkyl-C(O)—C 0-4 alkyl-R O , —C 0-3 alkyl-C(O)—C 0-4 alkyl-R P , —C(O)O—C 1-4 alkyl, —C 0-3 alkyl-C(O)O—C 0-4 alkyl-R O , —C 0-3 alkyl-C(O)O—C 0-4 alkyl-R P , —C 0-4 alkyl-C(O)OH, or —C 0-3 alkyl-C(O)—C 0-4 alkyl-NR M R N ;
 wherein:
 R L  is —C 1-4 alkyl, —C 3-5 cycloalkyl, —NR M R N ; 
 R M  and R N  are independently hydrogen, —C 1-4 alkyl, or R M  and R N  together with the atoms to which they are attached can form a 4- to 6-membered ring; 
 R O  is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, in each case monocyclic or bicyclic, and optionally substituted with (a) one to three moieties independently selected from —C 1-4 alkyl, halogen, —NR M R N , and —C 1-4 haloalkyl, or (b) a 6-membered aryl or 5-6 membered heteroaryl, optionally substituted with one to three moieties independently selected from —C 1-4 alkyl, halogen, and —NR M R N ; and 
 R P  is a 5- to 6-membered cycloalkyl or heterocycloalkyl group, optionally substituted with a hydroxyl; 
 
 provided that at least one of R 1A  and R 1B  is hydrogen; 
 
 R 2  is —C 5-6 cycloalkyl, —C 5-6 cycloalkyl-C 1-3 alkyl optionally substituted with a halogen, —C 5-6 cycloalkenyl, —C 5-6 cycloalkenyl-C 1-3 alkyl optionally substituted with a halogen or —C 1-4 alkyl-C 3-5 cycloalkyl; and 
 R 3  is —R A —R B  or halo;
 wherein R A  is ethynyl, or phenyl optionally substituted with one or two halogens, and 
 wherein R B  is hydrogen, —C 1-6 alkyl, —C 0-3 alkyl-NR M R N , —NHC 1-3 alkyl-R Q , —N(R U )C(O)—R Q , —C(O)NR U R Q , carboxyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 0-3 alkyl-C 3-6 cycloalkyl, —C 1-4 alkoxy, -methyl-(C 1-4 alkoxy) 1-2 , —C 0-3 alkyl-NR S R T , —C 3-7 cycloalkyl-C 0-3 alkyl-R Q , —C 0-4 alkyl-R Q , —C 2-6 alkynyR Q , or —C 2-4 alkenyl-R Q ;
 wherein R Q  is a 5- to 9-membered monocyclic or bicyclic aryl or heteroaryl or a 3- to 7-membered cycloalkyl or heterocycloalkyl, optionally substituted with one or two —C 1-3 alkyl or —NR M R N ; 
 R S  and R T  are each independently hydrogen or —C 1-4 alkyl, or one of R S  and R T  is hydrogen and the other is —C(O)-5- to 9-membered aryl or heteroaryl; and 
 R U  is hydrogen or —C 1-4 alkyl; 
 
 provided that, if R A  is phenyl, then R B  appears at the para or meta position relative to the thiophene moiety; and 
 
 R 4  is hydrogen, —C 1-4 alkyl, —C 1-4 alkyl-OC(O)O—C 1-4 alkyl, —C 1-4 alkyl-OC(O)—C 1-4 alkyl, —C 1-4 alkyl-OC(O)O—C 3-6 cycloalkyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl-, —C 0-3 alkyl-C 5-6 aryl, or —C 1-4 alkyl-NR U R V ;
 wherein R U  and R V  are independently hydrogen or —C 1-4 alkyl. 
 
 
     
     
         21 . A method according to  claim 20 , wherein R 4  is hydrogen. 
     
     
         22 . A method according to  claim 20 , further comprising administering to the host at least one other active agent selected from the group consisting of interferons, ribavirin, nucleoside HCV NS5B polymerase inhibitors, non-nucleoside HCV NS5B polymerase inhibitors, HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3 inhibitors, HCV NS3 helicase inhibitors, HCV NS4B inhibitors, and human cyclophilin inhibitors. 
     
     
         23 . A combination, comprising a compound having a structure according to Formula I, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 one of X and Y is —CH— and the other is —N—; 
 R 1A  and R 1B  are independently hydrogen, —C 1-4 alkyl, —C 1-4 alkyl-C 3-7 cycloalkyl, —C 0-3 alkyl-C 5-7 heterocycloalkyl, —C 1-4 hydroxyalkyl, —C 1-4 haloalkyl, —C 1-4 alkyl-O—C 1-4 alkyl, —S(O) 2 C 1-4 alkyl, —S(O) 2 —R P , —S(O) 2 C 5-7 aryl-C 0-3 alkyl, —C 1-4 alkyl-S(O) 2 R L , —C 2-4 alkyl-NR M R N , —C 1-4 alkyl-R O , —C 0-3 alkyl-R P , —C 0-3 alkyl-C(O)C 1-4 alkyl, —C 0-3 alkyl-C(O)—C 1-4 hydroxyalkyl, —C 0-3 alkyl-C(O)—C 0-4 alkyl-R O , —C 0-3 alkyl-C(O)—C 0-4 alkyl-R P , —C(O)O—C 1-4 alkyl, —C 0-3 alkyl-C(O)O—C 0-4 alkyl-R O , —C 0-3 alkyl-C(O)O—C 0-4 alkyl-R P , —C 0-4 alkyl-C(O)OH, or —C 0-3 alkyl-C(O)—C 0-4 alkyl-NR M R N ;
 wherein:
 R L  is —C 1-4 alkyl, —C 3-5 cycloalkyl, —NR M R N ; 
 R M  and R N  are independently hydrogen, —C 1-4 alkyl, or R M  and R N  together with the atoms to which they are attached can form a 4- to 6-membered ring; 
 R O  is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, in each case monocyclic or bicyclic, and optionally substituted with (a) one to three moieties independently selected from —C 1-4 alkyl, halogen, —NR M R N , and —C 1-4 haloalkyl, or (b) a 6-membered aryl or 5-6 membered heteroaryl, optionally substituted with one to three moieties independently selected from —C 1-4 alkyl, halogen, and —NR M R N ; and 
 R P  is a 5- to 6-membered cycloalkyl or heterocycloalkyl group, optionally substituted with a hydroxyl; 
 
 provided that at least one of R 1A  and R 1B  is hydrogen; 
 
 R 2  is —C 5-6 cycloalkyl, —C 5-6 cycloalkyl-C 1-3 alkyl optionally substituted with a halogen, —C 5-6 cycloalkenyl, —C 5-6 cycloalkenyl-C 1-3 alkyl optionally substituted with a halogen or —C 1-4 alkyl-C 3-5 cycloalkyl; and 
 R 3  is —R A —R B  or halo;
 wherein R A  is ethynyl, or phenyl optionally substituted with one or two halogens, and 
 wherein R B  is hydrogen, —C 1-6 alkyl, —C 0-3 alkyl-NR M R N , —NHC 1-3 alkyl-R Q , —N(R U )C(O)—R Q , —C(O)NR U R Q , carboxyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 0-3 alkyl-C 3-6 cycloalkyl, —C 1-4 alkoxy, -methyl-(C 1-4 alkoxy) 1-2 , —C 0-3 alkyl-NR S R T , —C 3-7 cycloalkyl-C 0-3 alkyl-R Q , —C 0-4 alkyl-R Q , —C 2-6 alkynyR Q , or —C 2-4 alkenyl-R Q ;
 wherein R Q  is a 5- to 9-membered monocyclic or bicyclic aryl or heteroaryl or a 3- to 7-membered cycloalkyl or heterocycloalkyl, optionally substituted with one or two —C 1-3 alkyl or —NR M R N ; 
 R S  and R T  are each independently hydrogen or —C 1-4 alkyl, or one of R S  and R T  is hydrogen and the other is —C(O)-5- to 9-membered aryl or heteroaryl; and 
 R U  is hydrogen or —C 1-4 alkyl; 
 
 provided that, if R A  is phenyl, then R B  appears at the para or meta position relative to the thiophene moiety; and 
 
 R 4  is hydrogen, —C 1-4 alkyl, —C 1-4 alkyl-OC(O)O—C 1-4 alkyl, —C 1-4 alkyl-OC(O)—C 1-4 alkyl, —C 1-4 alkyl-OC(O)O—C 3-6 cycloalkyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl-, —C 0-3 alkyl-C 5-6 aryl, or —C 1-4 alkyl-NR U R V ; 
 wherein R U  and R V  are independently hydrogen or —C 1-4 alkyl; 
 the compound together with at least one other active agent selected from the group consisting of interferons, ribavirin, nucleoside HCV NSSB polymerase inhibitors, non-nucleoside HCV NSSB polymerase inhibitors, HCV NS3-4A protease inhibitors, HCV NSSA inhibitors, HCV entry inhibitors, HCV NS3 inhibitors, HCV NS3 helicase inhibitors, HCV NS4B inhibitors, and human cyclophilin inhibitors.